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Gut-Pancreas-Liver Axis As a Target for Treatment of NAFLD/NASH

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Gut-Pancreas-Liver Axis As a Target for Treatment of NAFLD/NASH International Journal of Molecular Sciences Review Gut-Pancreas-Liver Axis as a Target for Treatment of NAFLD/NASH Gianluca Svegliati-Baroni 1,2,Bárbara Patrício 3,4,5 , Gessica Lioci 6, Maria Paula Macedo 5,7,8,* and Amalia Gastaldelli 3,4,* 1 Liver Injury and Transplant Unit, Ospedali Riuniti Ancona, 60020 Ancona, Italy; [email protected] 2 Obesity Center, Polytechnic University of Marche, 60121 Ancona, Italy 3 Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, 56124 Pisa, Italy; [email protected] 4 Institute of Life Sciences, Sant0Anna School of Advanced Studies, 56127 Pisa, Italy 5 APDP Diabetes Portugal, Education and Research Center (APDP-ERC), 1250-189 Lisbon, Portugal 6 Department of Gastroenterology, Polytechnic University of Marche, 60121 Ancona, Italy; [email protected] 7 CEDOC, NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1150-082 Lisboa, Portugal 8 Department of Medical Sciences, Institute of Biomedicine-iBiMED, University of Aveiro, 3810-193 Aveiro, Portugal * Correspondence: [email protected] (M.P.M.); [email protected] (A.G.); Tel.: +39-050-3152679/80 (A.G.) Received: 1 July 2020; Accepted: 9 August 2020; Published: 13 August 2020 Abstract: Non-alcoholic fatty liver disease (NAFLD) represents the most common form of chronic liver disease worldwide. Due to its association with obesity and diabetes and the fall in hepatitis C virus morbidity, cirrhosis in NAFLD is becoming the most frequent indication to liver transplantation, but the pathogenetic mechanisms are still not completely understood. The so-called gut-liver axis has gained enormous interest when data showed that its alteration can lead to NAFLD development and might favor the occurrence of non-alcoholic steatohepatitis (NASH). Moreover, several therapeutic approaches targeting the gut-pancreas-liver axis, e.g., incretins, showed promising results in NASH treatment. In this review, we describe the role of incretin hormones in NAFLD/NASH pathogenesis and treatment and how metagenomic/metabolomic alterations in the gut microbiota can lead to NASH in the presence of gut barrier modifications favoring the passage of bacteria or bacterial products in the portal circulation, i.e., bacterial translocation. Keywords: non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; type-2 diabetes; gut-pancreas-liver axis; incretins; lipid metabolism; glucose metabolism 1. Introduction The incidence of non-alcoholic fatty liver disease (NAFLD) is rapidly growing and it is estimated that in the general population about 25% of the individuals have hepatic steatosis [1]. The real prevalence of the disease is unknown, but it increases up to 57% in those with body mass index (BMI) of 30kg/m2 or greater (obesity), to 70% in diabetic subjects, and 90% in morbidly obese patients undergoing metabolic surgery [2,3]. The mechanisms that lead to hepatic triglyceride (TG) accumulation and the development of NASH are complex and still incompletely understood. It has been postulated that the initial accumulation of hepatic TG is a compensatory effect for hepatic lipid overflow without major metabolic effect (first hit). However, lipotoxicity and other factors are triggering hepatic inflammation and tissue fibrosis that can lead to non-alcoholic steatohepatitis (NASH, second hit) [4]. Several hypotheses Int. J. Mol. Sci. 2020, 21, 5820; doi:10.3390/ijms21165820 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2019, 20, x FOR PEER REVIEW 2 of 41 Int. J. Mol. Sci. 2020, 21, 5820 2 of 39 inflammation and tissue fibrosis that can lead to non-alcoholic steatohepatitis (NASH, second hit) [4]. Several hypotheses have been postulated as regard to the second hit, including the involvement of havean alteration been postulated in the gut-liver as regard axis to [5]. the The second intest hit,ine including is a multifunctional the involvement organ ofconnected an alteration with inmany the gut-liverbody organs axis but [5]. its The role intestine in metabolism is a multifunctional control was on organly revealed connected in recent with years. many The body intestinal organs cells but itssecrete role inseveral metabolism hormones—among control was only these revealed glucagon in recent-like years.peptide-1 The intestinal(GLP-1), cellsglucose-dependent secrete several hormones—amonginsulinotropic peptide these (GIP), glucagon-like oxyntomodulin peptide-1 and (GLP-1), possibly glucose-dependent glucagon—that insulinotropic are involved peptide with (GIP),pancreatic oxyntomodulin hormones insulin and possibly and glucagon glucagon—that and are areimportant involved for with the pancreaticmaintenance hormones of glucose insulin and andlipid glucagon homeostasis and are[6]. importantMoreover, for the the gut maintenance microbiota ofcan glucose influence and whole lipid homeostasis body and liver [6]. Moreover,metabolic theand gut inflammatory microbiota canstatus influence through whole the metabolism body and liver of nutrients metabolic and and the inflammatory release of statusanti- and through pro- theinflammatory metabolism compounds. of nutrients andThe theintestinal release ofbarrier anti- andmight pro-inflammatory become compromised compounds. allowing The intestinalbacterial barriertranslocation might becomefrom the compromised intestine to allowingother organs bacterial (the translocationliver in primis). from The the aim intestine of this to otherreview organs is to (thediscuss liver some in primis). of the The mechanisms aim of this involved review is toin discussthe gut-pancreas-liver some of the mechanisms axis important involved for in thethe gut-pancreas-liverdevelopment of NAFLD axis important and its progression for the development to NASH ofand NAFLD other comorbidities and its progression like type-2 to NASH diabetes and other(T2D). comorbidities like type-2 diabetes (T2D). 2.2. Physiological EEffectsffects ofof IncretinIncretin HormonesHormones ItIt isis nownow recognizedrecognized thatthat thethe intestineintestine isis anan endocrineendocrine organorgan ableable toto secretesecrete hormoneshormones thatthat regulateregulate whole-bodywhole-body metabolism metabolism in in response response to foodto fo ingestionod ingestion and alsoand toalso regulate to regulate appetite appetite and gastric and emptying.gastric emptying. Among Among these hormones, these hormones, the most the studied most arestudied the incretinare the hormonesincretin hormones like GLP-1 like and GLP-1 GIP thatand areGIP secreted that are mainlysecreted by mainly the intestine by the inintestine response in response to a meal to [7 ]a (Figure meal [7]1). (Figure 1). FigureFigure 1.1. SecretionSecretion andand physiological physiological e ffeffectsects of of incretin incretin hormones hormones GIP GIP and and GLP-1 GLP-1 in di inff erentdifferent organs organs and tissues.and tissues. The intestinalThe intestinal epithelium epithelium is composed is composed of several of cellseveral types, cell including types, including enteroendocrine enteroendocrine cells such ascells K-cells such and as L-cells,K-cells responsibleand L-cells, for responsible the secretion for of the GIP secretion and GLP-1, of GIP respectively. and GLP-1, The respectively. secretion of these The hormonessecretion of is triggeredthese hormones upon nutrient is triggered stimulation upon ofnu Gtrient protein-coupled stimulation receptorsof G protein-coupled (GPCRs) present receptors in the cell(GPCRs) membrane. present Some in the of cell the membrane. nutrients responsible Some of the for nutrients GIP and responsible GLP-1 secretion for GIP are and glucose GLP-1 (and secretion other carbohydrates),are glucose (and lipids, other some carbohydrates), amino acids lipids, and proteins. some amino Bile acids acids can and also proteins. stimulate Bile incretin acids secretion.can also Afterstimulate secretion, incretin GIP secretion. and GLP-1 After exert secretion, their functions GIP and in theGLP-1 pancreas exert andtheir extra-pancreatic functions in the tissues, pancreas such and as theextra-pancreatic liver, adipose tissue,tissues, muscle, such as bone, the and liver, the adip centralose nervous tissue, system.muscle, Abbreviations:bone, and the AA, central Amino nervous acids; CASR,system. Calcium-sensing Abbreviations: receptor;AA, Amin FFAR,o acids; Free CASR, fatty acid Calcium-sensing receptor; GIP, Glucose-dependent receptor; FFAR, Free insulinotropic fatty acid peptide;receptor; GLP-1, GIP, Glucose-dependent Glucagon-like peptide-1; insulinotropic GLP-2, Glucagon-like peptide; GLP-1, peptide-2; Glucagon-like GLUT, Glucose peptide-1; transporter; GLP-2, LCFA,Glucagon-like Long-chain peptide-2; fatty acids; GLUT, PYY, Glucose Peptide transporter; YY; SCFA, Short-chain LCFA, Long-chain fatty acids; fatty SGLT, acids; Sodium-dependent PYY, Peptide YY; glucose cotransporter; TGR5, Takeda G protein-coupled receptor 5; VLDL, Very-low-density lipoprotein. Int. J. Mol. Sci. 2020, 21, 5820 3 of 39 After secretion, gut hormones are rapidly degraded by dipeptidyl peptidase-4 (DPP-4), resulting in an in vivo half-life of approximately two minutes. DPP-4 is a 110 kilodaltons (kDa) membrane-associated peptidase that is expressed on the apical surface of epithelial and acinar cells, endothelial cells, fibroblasts, and lymphocytes [8–10] and also exists as a soluble circulating form in plasma [11]. For this reason, synthetic forms of GLP-1 resistant to the action of DPP-4 (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide) or inhibitors of DPP-4
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